Opioid is a collective term for alkaloid and synthetic or endogenous peptides having morphine-like activities such as narcotic analgesics and their related synthetic analgesics. As opioid receptors involved in the expression of action of opioids, four subtypes of μ, κ, δ, and ORL-1 are currently known. Among them, μ-opioid receptors are receptors that are most relevant to the action of morphine. In addition to morphine, fentanyl and methionine enkephalin and β-endorphin, which are endogenous opioids, also act on μ-opioid receptors.
Administration of morphine or fentanyl, which is a μ-opioid receptor agonist, causes itchiness. Also in animal experiments, morphine induces the act of scratching in spinal intrathecal administration to monkeys, administration to the medullary dorsal horn of rats, and intracisternal administration to mice. Further, itchiness of refractory pruritic diseases is improved by μ-opioid receptor antagonists, and therefore it is considered that activation of μ-opioid receptors by methionine enkephalin and β-endorphin, which are endogenous opioids, is involved in the occurrence of itchiness.
It has been confirmed in various clinical tests that μ-opioid receptor antagonists such as naltrexone suppresses itchiness in dialysis patients and patients with cholestatic liver cirrhosis. Therefore, the development of μ-opioid receptor antagonists as antipruritic drugs has been expected, but there has been no approved drugs until now. In addition, naltrexone has side effects such as nausea, vomiting, and hyperalgesia, such as abdominal pain, and diarrhea, and is therefore not necessarily satisfactory as an antipruritic drug (Non-Patent Literature 1). Therefore, there has been demand for the development of a μ-opioid receptor-selective drug that has few side effects and high safety.
Many 3-azabicyclo[3.1.0]hexane derivatives having μ-opioid receptor antagonistic action have heretofore been reported (Patent Literatures 1 to 15, Non-Patent Literatures 2 to 4), but all the compounds disclosed in these documents are different in structure from the compound according to the present invention.